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A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS)

Primary Purpose

Multiple Sclerosis

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
placebo
rituximab
Sponsored by
Genentech, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Sclerosis focused on measuring PPMS, Primary progressive MS, Primary progressive multiple sclerosis, Rituxan, MS

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Definitive diagnosis of PPMS Disease duration of ≥ 1 year EDSS at baseline between 2.0 and 6.5 points, inclusive Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that is due to lower extremity findings Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months: For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug Exclusion Criteria: Pregnancy or lactation Incompatibility with MRI Lack of peripheral venous access History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies Known active bacterial, viral, fungal, mycobacterial, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes zoster or simplex infections) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 30 days prior to screening or oral antibiotics within 14 days prior to screening History or presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis) History of cancer, including solid tumors and hematologic malignancies (except resected and fully resolved cutaneous basal cell and squamous cell carcinomas) History of alcohol or drug abuse within 6 months prior to screening History of or currently active primary or secondary immunodeficiency Significant cardiac or pulmonary disease (including obstructive pulmonary disease) Presence of other significant, uncontrolled cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease that might interfere with a subject's ability to participate and to complete approximately 2.5 years of study participation History or presence of MS relapse or exacerbation History or presence of vascular disease potentially affecting the brain or spinal cord (e.g., stroke, transient ischemic attack, carotid stenosis, aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation) History or presence of myelopathy due to spinal cord compression by disk or vertebral disease History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression) History of intracranial or intraspinal tumor (e.g., meningioma, glioma) History or presence of potential metabolic cause of myelopathy or encephalopathy (e.g., vitamin B12 deficiency, thyroid abnormalities) History or presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 [HTLV-1], or herpes zoster myelopathy) History of genetically inherited progressive CNS degenerative disorder (e.g., X-linked adrenoleukodystrophy, hereditary spastic paraparesis) Neuromyelitis optica History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sj�gren syndrome, Beh�et disease) History or presence of sarcoidosis Previous treatment with rituximab (MabThera(R)/Rituxan(R)) Previous treatment with lymphocyte-depleting therapies (e.g., cyclophosphamide, Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation), except mitoxantrone, which should not be used 12 months prior to randomization Treatment with an investigational agent within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization Receipt of a live vaccine within 30 days prior to randomization Systemic corticosteroid therapy within 30 days prior to randomization Treatment with IFN-β, glatiramer acetate, IVIg, or plasmapheresis within 60 days prior to randomization Treatment with non-lymphocyte-depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil [MMF], cyclosporine) within 90 days prior to randomization Statins or hormone replacement therapy started within 30 days prior to randomization

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    1

    2

    Arm Description

    Outcomes

    Primary Outcome Measures

    Time to Confirmed Disease Progression (CDP)
    Disease progression was assessed using the Expanded Disability Status Scale (EDSS), a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of greater than or equal to (≥) 1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score greater than (>) 5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. Those who did not meet criteria for CDP, completed treatment with only initial progression, or received an exclusionary therapy were censored at last EDSS assessment. Time to CDP was the time from randomization to initial disease progression, estimated using Kaplan-Meier (KM) analysis.
    Percentage of Participants With CDP
    Disease progression was assessed using the EDSS, a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of ≥1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score >5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. The percentage of participants with CDP was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100.

    Secondary Outcome Measures

    Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan
    Scheduled T2-weighted MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total volume of T2 (ie, hyperintense) brain lesions at each visit was documented. Missing Week 96 values were imputed using a last observation carried forward (LOCF) approach, while participants with missing Baseline values were excluded. The change in T2 lesion volume was calculated as [volume at Week 96 minus volume at Baseline] and expressed in cubic millimeters (mm^3).
    Change From Baseline to Week 96 in Brain Volume on MRI Scan
    Scheduled MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total brain volume was documented at Baseline and at visits occurring during Weeks 48 and 96. Missing Week 96 values were imputed using a LOCF approach, while participants with missing Baseline values were excluded. The change in brain volume was calculated as [volume at Week 96 minus volume at Baseline] and expressed in cubic centimeters (cm^3).

    Full Information

    First Posted
    July 9, 2004
    Last Updated
    August 10, 2015
    Sponsor
    Genentech, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00087529
    Brief Title
    A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis
    Acronym
    OLYMPUS
    Official Title
    A Phase II/III, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2015
    Overall Recruitment Status
    Completed
    Study Start Date
    June 2004 (undefined)
    Primary Completion Date
    October 2007 (Actual)
    Study Completion Date
    undefined (undefined)

    3. Sponsor/Collaborators

    Name of the Sponsor
    Genentech, Inc.

    4. Oversight

    5. Study Description

    Brief Summary
    This is a Phase II/III, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with PPMS. The study will enroll approximately 435 subjects at up to 60 sites in the United States and Canada.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Multiple Sclerosis
    Keywords
    PPMS, Primary progressive MS, Primary progressive multiple sclerosis, Rituxan, MS

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2, Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    439 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    1
    Arm Type
    Experimental
    Arm Title
    2
    Arm Type
    Placebo Comparator
    Intervention Type
    Drug
    Intervention Name(s)
    placebo
    Intervention Description
    Intravenous repeating dose
    Intervention Type
    Drug
    Intervention Name(s)
    rituximab
    Intervention Description
    Intravenous repeating dose
    Primary Outcome Measure Information:
    Title
    Time to Confirmed Disease Progression (CDP)
    Description
    Disease progression was assessed using the Expanded Disability Status Scale (EDSS), a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of greater than or equal to (≥) 1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score greater than (>) 5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. Those who did not meet criteria for CDP, completed treatment with only initial progression, or received an exclusionary therapy were censored at last EDSS assessment. Time to CDP was the time from randomization to initial disease progression, estimated using Kaplan-Meier (KM) analysis.
    Time Frame
    96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)
    Title
    Percentage of Participants With CDP
    Description
    Disease progression was assessed using the EDSS, a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of ≥1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score >5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. The percentage of participants with CDP was calculated as [number of participants meeting the above criteria divided by the number analyzed] multiplied by 100.
    Time Frame
    96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)
    Secondary Outcome Measure Information:
    Title
    Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan
    Description
    Scheduled T2-weighted MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total volume of T2 (ie, hyperintense) brain lesions at each visit was documented. Missing Week 96 values were imputed using a last observation carried forward (LOCF) approach, while participants with missing Baseline values were excluded. The change in T2 lesion volume was calculated as [volume at Week 96 minus volume at Baseline] and expressed in cubic millimeters (mm^3).
    Time Frame
    At Baseline and Week 96
    Title
    Change From Baseline to Week 96 in Brain Volume on MRI Scan
    Description
    Scheduled MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total brain volume was documented at Baseline and at visits occurring during Weeks 48 and 96. Missing Week 96 values were imputed using a LOCF approach, while participants with missing Baseline values were excluded. The change in brain volume was calculated as [volume at Week 96 minus volume at Baseline] and expressed in cubic centimeters (cm^3).
    Time Frame
    At Baseline and Week 96

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Definitive diagnosis of PPMS Disease duration of ≥ 1 year EDSS at baseline between 2.0 and 6.5 points, inclusive Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that is due to lower extremity findings Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months: For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug Exclusion Criteria: Pregnancy or lactation Incompatibility with MRI Lack of peripheral venous access History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies Known active bacterial, viral, fungal, mycobacterial, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes zoster or simplex infections) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 30 days prior to screening or oral antibiotics within 14 days prior to screening History or presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis) History of cancer, including solid tumors and hematologic malignancies (except resected and fully resolved cutaneous basal cell and squamous cell carcinomas) History of alcohol or drug abuse within 6 months prior to screening History of or currently active primary or secondary immunodeficiency Significant cardiac or pulmonary disease (including obstructive pulmonary disease) Presence of other significant, uncontrolled cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease that might interfere with a subject's ability to participate and to complete approximately 2.5 years of study participation History or presence of MS relapse or exacerbation History or presence of vascular disease potentially affecting the brain or spinal cord (e.g., stroke, transient ischemic attack, carotid stenosis, aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation) History or presence of myelopathy due to spinal cord compression by disk or vertebral disease History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression) History of intracranial or intraspinal tumor (e.g., meningioma, glioma) History or presence of potential metabolic cause of myelopathy or encephalopathy (e.g., vitamin B12 deficiency, thyroid abnormalities) History or presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 [HTLV-1], or herpes zoster myelopathy) History of genetically inherited progressive CNS degenerative disorder (e.g., X-linked adrenoleukodystrophy, hereditary spastic paraparesis) Neuromyelitis optica History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sj�gren syndrome, Beh�et disease) History or presence of sarcoidosis Previous treatment with rituximab (MabThera(R)/Rituxan(R)) Previous treatment with lymphocyte-depleting therapies (e.g., cyclophosphamide, Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation), except mitoxantrone, which should not be used 12 months prior to randomization Treatment with an investigational agent within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization Receipt of a live vaccine within 30 days prior to randomization Systemic corticosteroid therapy within 30 days prior to randomization Treatment with IFN-β, glatiramer acetate, IVIg, or plasmapheresis within 60 days prior to randomization Treatment with non-lymphocyte-depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil [MMF], cyclosporine) within 90 days prior to randomization Statins or hormone replacement therapy started within 30 days prior to randomization
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Craig Smith, M.D.
    Organizational Affiliation
    Genentech, Inc.
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    23027880
    Citation
    Zhang J, Waubant E, Cutter G, Wolinsky JS, Glanzman R. EDSS variability before randomization may limit treatment discovery in primary progressive MS. Mult Scler. 2013 May;19(6):775-81. doi: 10.1177/1352458512459685. Epub 2012 Oct 1.
    Results Reference
    derived
    PubMed Identifier
    19847908
    Citation
    Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, Hauser S, Waubant E, Vollmer T, Panitch H, Zhang J, Chin P, Smith CH; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460-71. doi: 10.1002/ana.21867.
    Results Reference
    derived

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    A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis

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